The effect of hydroxypropyl-beta-cyclodextrin and sucrose on the sublingual absorption of midazolam in rabbits

Sublingually administered midazolam is commonly used for premedication of pediatric patients. However, the irritating taste and low aqueous solubility of midazolam complicate its sublingual use. Cyclodextrin complexation can be used to improve both the taste and aqueous solubility of drugs, but based on earlier studies, the complexation efficiency of midazolam is relatively low. In the present study, the complexation of midazolam with hydroxypropyl-beta-cyclodextrin (HP-β-CD) was investigated in the presence of various excipients. The aqueous solubility of midazolam improved significantly when HP-β-CD was used together with sucrose. Sucrose alone did not increase the solubility of midazolam. In addition, sucrose increased the apparent stability constant of the midazolam/HP-β-CD complex. The pharmacokinetics of midazolam in different dosage forms was investigated in rabbits (dose 1 mg/rabbit) after intravenous administration of midazolam solution and after sublingual administration of midazolam solution, midazolam/HP-β-CD/sucrose solution or midazolam/HP-β-CD/sucrose powder. Midazolam displayed rapid sublingual absorption (mean tmax ⩽ 30 min from the liquid formulations and 60 min from the solid formulation) with high absolute bioavailability (>68%) from all evaluated formulations. Based on the results, HP-β-CD and sucrose can be utilized together to prepare more concentrated and palatable midazolam formulations for sublingual administration in pediatric patients.

The combined use of hydroxypropyl-beta-cyclodextrin (HP-β-CD) and sucrose significantly improved the aqueous solubility of midazolam. Midazolam was rapidly and substantially absorbed in rabbits from liquid and solid formulations containing midazolam, HP-β-CD, and sucrose. This synergistic solubilization of midazolam may be utilized in the preparation of more concentrated and better palatable midazolam formulations for pediatric patients.Figure optionsDownload high-quality image (55 K)Download as PowerPoint slide